Idiopathic pulmonary alveolar proteinosis (PAP) is a rare lung disease of unknown etiology. PAP is characterized by the accumulation in the alveoli of surfactant material, which is thought to result from inefficient catabolism by alveolar macrophages and type II epithelial cells. The granulocyte macrophage-colony stimulating factor (GM-CSF) knockout mouse develops a PAP like syndrome, which can be resolved by pulmonary expression of GM-CSF. These observations led to the treatment of PAP patients with recombinant GM-CSF with a subset showing improvement of lung disease. Subsequently, it was determined that all untreated PAP patients had neutralizing antibodies against GM-CSF. In this context, PAP is an excellent disease model to illustrate surfactant catabolism and lung homeostasis as well as the dynamic relationship between the "bench" and the "bedside." Further, the integration of observations in the GM-CSF knockout mouse, to ex vivo studies at the bench, to dynamic in vivo PAP patient management decisions is an excellent foundation for the development of an independent "patient-oriented" scientist. In the GM-CSF knockout mouse, it has been shown that GM-CSF regulates monocyte/macrophage surfactant catabolism through the transcription factor PU.1. GM-CSF can induce activation and differentiation of monocyte/macrophages through peroxisome proliferator-receptor (PPAR() which has not been evaluated in alveolar macrophages. Our preliminary data shows that (1) anti-GM-CSF titer is diagnostic for PAP and it correlates with PAP disease activity in vivo (2) PAP alveolar macrophages ex vivo express less PU.1 and PPAR( than healthy control alveolar macrophages, (3) PAP alveolar macrophages ex vivo express less of differentiation markers CD14, TLR2, TLR4 and MR while the expression of certain pro-inflammatory cytokines GM-CSF, IL-6 and MIP-1a are elevated as compared to healthy controls. Based upon these data, we hypothesize that maturation and differentiation of human alveolar macrophages by GM-CSF through the activation of PPAR( and PU.1 is essential for surfactant catabolism. The specific aims are: (1) Evaluate the role of GM-CSF in regulating PPAR( and PU.1 in alveolar macrophage maturation, differentiation and surfactant catabolism; (2) To use the ongoing GM-CSF-FDA clinical trial to evaluate changes in functional GM-CSF on monocyte/macrophage maturation, differentiation and surfactant catabolism. The translational focus of this proposal provides an ideal training environment for the development of "patient-oriented" investigative skills. Laboratory observations will be interfaced with patient clinical course, thus contributing to dynamic patient management decisions. These studies are the first to address the role of GM-CSF in alveolar macrophage maturation, differentiation and surfactant catabolism and have the unique advantage of utilizing PAP patients involved in a FDA approved GM-CSF clinical trial as an in vivo model.